This invention relates to a method of treating allergy, particularly immediate hypersensitivity, and to pharmaceutical compositions useful therefor.
Immediate hypersensitivity, that is, anaphylactic response, is a form of allergic reaction which develops very quickly, i.e., within seconds or minutes of exposure of the patient to the causative allergen and which is mediated by IgE antibodies made by B lymphocytes. There is very little IgE in non-allergic patients, but in a person suffering from allergy, the concentration of IgE is very much higher. This elevated amount of IgE mediates immediate hypersensitivity by priming mast cells which are abundant in the skin, lymphoid organs, membranes of the eye, nose and mouth, and respiratory tree and intestines. Mast cells have surface IgE receptors, and the elevated concentrations of IgE in allergy-suffering patients become bound to them. When this bound IgE is subsequently contacted by the appropriate allergen, the mast cell is caused to degranulate and release various substances such as histamine into the surrounding tissue. It is the release of these substances which is responsible for the clinical symptoms typical of immediate hypersensitivity, namely, contraction of smooth muscle in the airways or the intestine, the dilation of small blood vessels and increase in their permeability to water and plasma proteins, secretion of thick, sticky mucus and, in the skin, the stimulation of nerve endings that results in itching or pain.
Immediate hypersensitivity is, at best, a nuisance to the sufferer. At worst it can present very serious problems and can in rare, extreme cases result in death. Efforts have been made for many years to find some way of effectively treating sufferers, and essentially three such ways have been found. These are: avoidance of the allergen, desensitization and the use of drugs. Of these, avoidance of the allergen is in one sense clearly the best approach, but of course, it is in practice very difficult, and usually impossible, to achieve. Treatment by the use of drugs is useful, but it is generally directed to alleviating the symptoms of allergy rather than dealing with its causes. Also, there are disadvantages in the use of certain drugs, and it is by no means always possible with drugs to assist patients to the extent desired.
The third method of treatment, namely, desensitization, has long been recognized as perhaps the most hopeful practical approach to the problem. It has been known for over 60 years that the injection into a patient of initially small but subsequently increasing amounts of the offending allergen itself, over a period of time, can often result in an improved resistance to that allergen. This procedure is known as "desensitization" or "allergen immunotherapy". While it is not useful in the treatment of food allergies, it is useful in the treatment of, for example, inhalant allergen-derived sensitivity and allergic reactions due to insect stings.
Curiously, although desensitization has been successfully practiced for many years, the mechanism by which it works is still not known. In most patients, the injection of the allergen appears to give rise, not to IgE antibodies, but rather to IgG antibodies which, upon inhalation by the patient of the allergen in question, combine with the allergen to block its ability to bind to the mast cell IgE. These IgG antibodies are called "blocking antibodies". However, this hypothesis does not always fit the facts. In some patients who are successfully desensitized, there is little specific IgG in their blood, and in other patients for whom the injections have apparently been ineffective against allergy, there is a large amount of the particular IgG.
Whatever the mechanism may be, it remains the fact that many though not all sufferers of immediate hypersensitivity can be helped considerably by desensitization. The technique involves injecting the allergen to which the patient has become sensitized into the patient over a relatively long period of time, e.g., one year or more. Initially, the doses used are very small, but in the absence of contra-indications, they are increased rapidly to high levels which are necessary if the treatment is to be effective.
There are certain problems in desensitization treatment. First, it is necessary for the patient to have injections very frequently, e.g., initially every two or three days, gradually reducing to once every two or three weeks. This is not only a time-consuming procedure, but is also disruptive of the patient's normal routine, and generally undesirable. Also, the dose of allergen administered has to be carefully monitored and controlled, which adds to the complexity of the procedure. A second problem is that, in the treatment itself, there is an element of risk to the patient. Even though initial doses of the allergen are very small and precautions are routinely taken to watch for any allergic response, local or systemic allergic reactions such as hives, asthma and fainting do sometimes occur and can cause death in exceptional cases. For these and other reasons, many practicing physicians are skeptical of desensitization techniques.
Attempts have been made in the past to overcome or avoid these problems. To reduce the frequency of injection, preparations have been administered which release the allergen slowly over a period of time. These have not been very successful for a number of reasons, an important one of which being that, once administered, no control can be exercised over the amount of allergen released into the patient's blood. Another way in which the frequency of injection might be reduced would be to devise a treatment whereby the necessary large doses of allergen are administered rather earlier to the patient, but to date there has been no such treatment devised. Attention is also being directed to the possibility of administering modified allergens instead of the "pure" material itself. Thus, attempts have been made to modify an allergen chemically so that, while its immunogenicity, i.e., its ability to cause an immune response in the patient, is unchanged, its allergenicity is substantially reduced. Success has been achieved with this approach, but it has certain disadvantages of its own. First, each allergen, and there are of course a vast number of allergens against which patients can become sensitized and thus need desensitization treatment, has to be modified individually in accordance with its particular chemical structure, such that there is no satisfactory, universally applicable technique for modifying allergens for a desensitization treatment. Second, a very considerable amount of work can be involved in devising an acceptable modified allergen, bearing in mind the requirements for it to be useful in the desensitization treatment, including the necessity for the chemical modification itself not to cause any adverse reaction in the patient. Third, because accurate control of dose is so important in a desensitization treatment, there can be problems with modified allergens in determining the proper dose required.
Further background information on allergy and desensitization treatments may be found in Paul D. Buiseret, "Allergy", Scientific American, August 1982, pp. 82-91; Howard J. Sanders, "Allergy: A Protective Mechanism Out of Control", C & E News, vol 48, pp. 84-134 (1970); and "Primer on Allergic and Immunologic Disease", Journal of the American Medical Association, volume 248, no. 20 (Nov. 26, 1982).